Laboratory of Viral & Gene Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai 200438, China.
Gut. 2011 May;60(5):710-21. doi: 10.1136/gut.2010.220020. Epub 2010 Oct 22.
Hepatocellular carcinoma (HCC) is one of the most malignant tumours with high rate of recurrence and metastasis. In HCC, deficiency of the P16/CDK4/Rb pathway is a frequent molecular event, and transferring the P16 gene into cancer cells can induce cell cycle arrest and apoptosis, suggesting that the P16 gene is a good target in cancer gene therapy. The previous study demonstrated that P16 re-expression mediated by adenovirus within cancer cells can induce cell apoptosis and exert potent antitumour efficacy in cancer xenografts in nude mice. However, the molecular mechanism of P16-induced apoptosis in cancer cells is not clear yet. In this resulting study, we found that P16 re-expression can downregulate survivin expression in HCC cells. As a member of the inhibitors of the apoptotic gene family, survivin has been reported to be overexpressed in most common human cancers and present multiple physiological and pathological functions including cell cycle control, inhibition of cell apoptosis, regulation of cell division and induction of angiogenesis, etc. Further investigation found that P16 reactivation led to a decrease of phosphorylated Akt on Thr308 and phosphorylated survivin on Thr34, then downregulated survivin expression. The P16-mediated decrease of nuclear survivin in cancer cells limited CDK4 import into nuclei, which restrained CDK4 functions of promoting cell proliferation, then exhibited the effect of cell cycle arrest and induction of detachment-induced apoptosis (anoikis). The antitumor potency of P16 by downregulating the Akt/survivin signalling was also demonstrated in HCC xenograft models in nude mice. This new insight into P16 function would help in designing better strategies for cancer gene therapy.
肝细胞癌（HCC）是恶性程度最高的肿瘤之一，其复发和转移率很高。在 HCC 中，P16/CDK4/Rb 通路缺陷是一种常见的分子事件，将 P16 基因转入癌细胞可诱导细胞周期停滞和细胞凋亡，提示 P16 基因是癌症基因治疗的一个良好靶点。先前的研究表明，腺病毒介导的癌细胞内 P16 再表达可诱导细胞凋亡，并在裸鼠的 HCC 异种移植模型中发挥强大的抗肿瘤作用。然而，P16 诱导癌细胞凋亡的分子机制尚不清楚。在本研究中，我们发现 P16 再表达可下调 HCC 细胞中 survivin 的表达。作为凋亡基因家族抑制剂的一员，survivin 已在大多数常见的人类癌症中过表达，并具有多种生理和病理功能，包括细胞周期调控、抑制细胞凋亡、调节细胞分裂和诱导血管生成等。进一步的研究发现，P16 再激活导致 Thr308 上磷酸化 Akt 和 Thr34 上磷酸化 survivin 的减少，进而下调 survivin 的表达。癌细胞中核内 survivin 的减少限制了 CDK4 向核内的导入，从而抑制了 CDK4 促进细胞增殖的功能，从而表现出细胞周期停滞和诱导脱落诱导凋亡（凋亡）的作用。下调 Akt/survivin 信号通路的 P16 在裸鼠 HCC 异种移植模型中也显示出抗肿瘤作用。对 P16 功能的这一新认识将有助于设计更好的癌症基因治疗策略。
